Abstract 19117: Mice Generated by Assisted Reproductive Technologies, a Model Organism for the Study of Epigenetic Mechanisms of Vascular Dysfunction in vivo
Background: Environmental influences acting early in life predispose to premature cardiovascular disease. Assisted reproductive technologies (ART) involve the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. We recently found that vascular function in both children and mice conceived by ART is defective. In mice, this vascular dysfunction is transmitted to their progeny, suggesting an epigenetic mechanism.
Methods: To test this hypothesis, we assessed vascular function and the vascular DNA methylation pattern of imprinted genes and the eNOS gene promoter in male ART and control mice. We then tested the effects of a histone deacetylase inhibitor on these variables.
Results: As expected, ART mice displayed marked mesenteric-artery endothelial dysfunction in vitro and arterial hypertension in vivo. Most importantly, the methylation pattern of imprinted genes H19 (P<.01, vs. ctrl), Gtl2 (P<.01, vs. ctrl), Peg3 (P=.02, vs. ctrl) and of the eNOS promoter (P=.01, vs. ctrl) was altered in the aorta of ART mice. The dysmethylation of the eNOS gene promoter in ART mice was of functional importance, since it was associated with decreased eNOS expression in carotid arteries and decreased NOx plasma concentration (9.1±10.4 vs. 32.3±9.6 μM, X±SD, P<.001, ART vs. ctrl). DNA dysmethylation can be reversed by histone deacetylase inhibitors. Administration of such an inhibitor (Butyrate, 2 mg/kg/d, i.p. for 2 wks) to male ART mice normalized the vascular methylation pattern of imprinted genes H19, Gtl2 and Peg3 (all P<.05 vs. vehicle), of the eNOS promoter (P=.04 vs. vehicle) and NOx plasma concentration (29.0±12.4 μM, P<.0001 vs. vehicle). The normalization of the vascular DNA methylation pattern by Butyrate was associated with normalization of the vascular function in ART mice and prevention of the transmission of this defect to their progeny.
Conclusions: ART induces premature systemic vascular dysfunction in mice by an epigenetic mechanism. ART mice represent a model organism for the study of epigenetic mechanisms of vascular dysfunction. We speculate that epigenetic mechanisms also play a role in ART-induced vascular dysfunction and predisposition to premature cardiovascular disease in humans.
- © 2010 by American Heart Association, Inc.